Metals such as manganese and arsenic are of increasing public health concern since recent data demonstrates their neurotoxicity to the developing brain. However, the role of genetic susceptibility to these toxic metals is unknown. Furthermore, while lead poisoning has been studied extensively, genetic susceptibility to its toxicity is not well understood. A systematic approach to studying gene-environment interaction would have immediate impact on our understanding of how metals induce toxicity and provide biological insight for potential treatment and prevention measures. In this project we will assess data from 3 cohort studies of metals and neurodevelopment. One in a developing country-Bangladesh, where metal exposures are unusually high, one in Mexico, a middle income country where metal exposures are moderately high, and one in a developed Country- (United States) in Tar Creek, OK, where exposure are representative of a community near a US toxic waste site. Tar Creek is a Superfund Megasite and former metal mining community. The success in assembling these cohorts has laid the groundwork for further research in genetic susceptibility to metals. Our 3 cohorts combined yield a sample of 2600 children with prospective data on metal exposure, and repeated neurophenotype measures; sufficient power to discover and to validate genetic susceptibility genes/SNPs. Using a genome-wide approach, we will discover susceptibility variants in a Discovery phase, and then Validate our findings in an independent sample of children while controlling for multiple comparisons. Furthermore, we will integrate with Project 3 (Genetic Mechanisms of Metal Neurotoxicity) to determine other biological pathways relevant to metal toxicity using state of the art siRNA technology to identify genes/pathways which promote/inhibit metal toxicity. This project represents perhaps the first large scale coordinated study of genetic susceptibility to metal toxicity and will provide biological insight into the mechanisms by which metals produce toxicity.